Research is proposed to: 1) investigate the role of monoaminergic mechanisms in the behavioral effects of cocaine relevant to its abuse; 2) characterize interactions between cocaine and opioids acting at different opioid receptors subtypes; and 3) evaluate the effectiveness of candidate therapeutics for counteracting cocaine's behavioral effects. Pharmacological studies will be conducted using schedule-controlled behavior, drug-discrimination techniques and i.v. self-administration procedures in nonhuman primates as experimental counterparts of the stimulant, subjective, and reinforcing effects of drugs in people. Research to investigate monoaminergic mechanisms in the abuse-related effects of cocaine will determine the degree to which selective noradrenergic and serotonergic uptake inhibitors and receptors ligands modulate cocaine's characteristic effects on behavior. Research to investigate cocaine-opioid interactions will determine how the behavioral effects of cocaine are modified by treatment with selective mu, kappa and delta receptor ligands. Research to evaluate candidate cocaine antagonists will determine the effectiveness of selected dopamine partial agonists, atypical neuroleptics, noradrenergic and serotonergic compounds, and kappa opioid agonists to counteract the behavioral effects of cocaine. Overall, the proposed research is designed to provide needed information on pharmacological factors mediating the abuse-related effects of cocaine and cocaine-opioid combinations and to evaluate how modulation of different monoaminergic and opioid receptor systems might be exploited in the development of effective therapeutics for cocaine abuse